Sulfated Non-Anticoagulant Heparin Nanoparticle (VVP728) for Sickle Cell Disease Management

用于镰状细胞病管理的硫酸化非抗凝肝素纳米颗粒 (VVP728)

• 批准号: 10545218
• 负责人: Bozena Korczak
• 金额: $ 99.62万
• 依托单位: VASCULAR VISION PHARMACEUTICALS COMPANY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545218
• 关键词: Accounting; Adhesions; Adopted; Affect; African American; African American population; Binding Proteins; Blood Transfusion; Blood Vessels; Cardiovascular system; Cells; Cessation of life; Chronic; Clinical; Complex; Data; Development; Disease; Disease Management; Disease Progression; Dose; Dose-Limiting; Endothelium; FDA approved; Fatigue; Frequencies; Functional disorder; Genotype; Glutamine; Hematopoietic Stem Cell Transplantation; Hemochromatosis; Hemoglobin concentration result; Hemorrhage; Heparin; Hispanic Americans; Hospitalization; In Vitro; Individual; Inflammation; Lead; Life Expectancy; Low-Molecular-Weight Heparin; Methods; Micronucleus Tests; Morbidity - disease rate; Mutation; Neuraxis; Organ; Organ failure; Oxides; Pain; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II/III Trial; Physiological; Property; Quality of life; Rattus; Relaxation; Research; Resolution; Rodent; Safety; Selectins; Sickle Cell Anemia; Sickle Cell Trait; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Sulfate; Testing; Therapeutic; Toxic effect; Toxicology; Treatment Cost; United Nations; Vascular Diseases; Vision; World Health Organization; alternative treatment; cost; disorder prevention; first-in-human; genotoxicity; global health; health disparity; hydroxyurea; improved; in vivo; manufacturing scale-up; mortality; mouse model; multimodality; nanoformulation; nanoparticle; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; polymerization; pre-clinical; preclinical study; premature; public health priorities; respiratory; secondary endpoint; stroke risk; subcutaneous; therapeutic candidate; treatment strategy; vaso-occlusive crisis

Summary: Sickle cell disease (SCD) primarily afflicts African-Americans in the US, exacerbating an existing health disparity. Approximately 1 in 13 African-American babies is born with the sickle cell trait and ~100,000 individuals live with SCD. Along with a range of adverse physiological effects resulting in painful vaso-occlusive crises (VOC), patients suffer from poorer quality of life and a significantly decreased life expectancy (only 54 years). A handful of drugs are currently FDA approved; however, despite their benefits, there are drawbacks. Hydroxyurea is effective for two genotypes accounting for only 60% of SCD patients and the frequency of painful episodes is reduced by only 50%. Newer drugs (L-glutamine, crizanlizumab, voxelotor) lack improvement in hemoglobin levels or lack reduction in number of VOCs. Alternative treatments, such as chronic blood transfusion therapy or hematopoietic stem cell transplantation, can provide benefit but can also lead to serious complications or impose roadblocks including cost and finding matching donors. There is a significant unmet need for potent, novel multi-modal SCD therapeutics that achieve optimal efficacy, safety, and quality of life. To meet this need, Vascular Vision proposes a sulfated oxidized non-anticoagulant low molecular weight heparin (S-NACH) to provide an extensive range of bioactivities without causing bleeding, a common dose limiting effect associated with the clinical use of low molecular weight heparins. Proof-of-concept in vitro and in vivo preclinical studies have established efficacy through multiple modes including anti-adhesion, anti-inflammation, anti-sickling, vascular antithrombotic, and endothelial relaxation. Our subcutaneous nanoformulation (VVP728) demonstrated improved SCD pharmacodynamics. This SBIR Phase II proposes IND-enabling studies to determine tolerability of nanoformulated S-NACH (VVP728) in support of first in human trials (FIH) through the following Specific Aims: Aim 1. Scale up manufacturing to establish PK/PD and support IND-enabling studies. To support preclinical PK/PD and GLP toxicology testing, we will scale up the manufacturing of research grade drug substance (DS: S-NACH) and drug product (DP: VVP728). Milestones: (1) Develop analytical and bioanalytical methods, (2) Deliver research grade DS (2 kg) and DP (1.5 kg) under GLP, and (3) Determine PK and vascular antithrombotic activity in rats and PD in Townes SCD mouse model for DS vs DP. Aim 2: Determine GLP safety profile of S-NACH. We will conduct dose range finding studies (7 days) and GLP repeated dose studies (28 days) in rodent (rat) and non-rodent (dog) as well as in vitro assessments of protein binding, transporter and CYP inhibition, effect on hERG current in transfected HEK-293 cells, and genotoxicity. In vivo central nervous system (CNS: rats), respiratory (dogs), and cardiovascular (dogs) assessments will be completed. Milestones: (1) Establish protein binding and potential for inhibition of transporters and CYPs by S-NACH, (2) Identify target organs of toxicity to inform selection of dose in FIH study, and (3) Establish genotoxic potential of S-NACH in Bacterial-Reverse Mutation and In Vitro Micronucleus Assays.

摘要：镰状细胞病（SCD）主要困扰美国的非洲裔美国人，加剧了现有的 健康差距。大约每13个非洲裔美国婴儿中就有1个出生时患有镰状细胞性状， 个人生活与SCD。沿着一系列不良生理作用，导致疼痛性血管闭塞 在VOC危机（VOC）中，患者的生活质量较差，预期寿命显着下降（仅54 年）。目前有少数药物获得了FDA的批准;然而，尽管它们有好处，但也有缺点。 羟基脲对两种基因型有效，仅占SCD患者的60%， 发作次数仅减少了50%。较新的药物（L-谷氨酰胺，crizanlizumab，voxelotor）缺乏改善， 血红蛋白水平或VOC数量缺乏减少。替代治疗，如长期输血 治疗或造血干细胞移植，可以提供好处，但也可能导致严重的并发症 或者设置障碍，包括成本和寻找匹配的捐赠者。对于强效的， 新型多模式SCD疗法，可实现最佳疗效、安全性和生活质量。为了满足这一需求， Vascular Vision提出了一种硫酸化氧化非抗凝低分子量肝素（S-NACH）， 提供广泛的生物活性，而不会引起出血，这是一种常见的剂量限制效应， 低分子量肝素的临床应用。体外和体内临床前研究的概念验证 通过抗粘连、抗炎、抗镰状化、 血管抗血栓和内皮松弛。我们的皮下纳米制剂（VVP 728）证明 改善SCD药效学。该SBIR II期建议进行IND使能研究，以确定耐受性 纳米配方S-NACH（VVP 728）通过以下特定目的支持首次人体试验（FIH）： 目标1。扩大生产规模以确定PK/PD并支持IND使能研究。支持 临床前PK/PD和GLP毒理学测试，我们将扩大研究级药物的生产 物质（DS：S-NACH）和制剂（DP：VVP 728）。军事：（1）开发分析和生物分析 方法，（2）根据GLP递送研究级DS（2 kg）和DP（1.5 kg），以及（3）确定PK和血管 DS与DP在大鼠中的抗血栓形成活性和Townes SCD小鼠模型中的PD。目的2：确定GLP安全性 关于S-NACH我们将进行剂量范围探索研究（7天）和GLP重复给药研究（28 以及体外评估蛋白结合、转运蛋白和 转染HEK-293细胞中的hERG电流抑制作用和遗传毒性。体内中枢神经 将完成系统（CNS：大鼠）、呼吸系统（犬）和心血管系统（犬）评估。重要事件： (1)确定蛋白结合以及S-NACH抑制转运蛋白和CYP的潜力，（2）确定靶点 毒性器官，以告知FIH研究中的剂量选择，和（3）确定S-NACH在 细菌回复突变和体外微核试验。